Report Expression of Senescence and Apoptosis Biomarkers ...
Case Report
Expression of Senescence and Apoptosis Biomarkers in Syn\
chronous Bilateral Breast Cancer: A Case Report
Tareq Saleh 1,*, Mohammed El\Sadoni 2,?, Ahmad Alhesa 2,?, Heyam Awad 2, Mahmoud Jaradat 3,
Mohammad Al\hazaimeh 3, Rand Dawoud 1, Amel Mryyian 1 and Bilal Azab 2,4
Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan;
1636586@std.hu.edu.jo (R.D.); 1635542@std.hu.edu.jo (A.M.)
2 Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jor\
dan, Amman 11942, Jordan; mhm8191130@ju.edu.jo (M.E.\S.); ahm8171602@ju.edu.jo (A.A.);
h_awad@ju.edu.jo (H.A.); ba2659@cumc.columbia.edu (B.A.)
3 Department of General Surgery, Jordanian Royal Medical Services, Amman 11942, Jordan; mahmodjara\
dat@ (M.J.); dr.hazaimeh88.mh@ (M.A.\h.)
4 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York,
NY 10032, USA
* Correspondence: tareq@hu.edu.jo; Tel.: +962\53903333 (ext. 5574)
? Authors contributed equally to this work.
1
Citation: Saleh, T.; El\Sadoni, M.;
Alhesa, A.; Awad, H.; Jaradat, M.;
Al\hazaimeh, M.; Dawoud, R.;
Mryyian, A.; Azab, B. Expression of
Senescence and Apoptosis Bi\
omarkers in Synchronous Bilateral
Breast Cancer: A Case Report. Curr.
Oncol. 2021, 28, 3836C3845.
\
Abstract: Background: Synchronous bilateral breast cancer (SBBC) provides a special condition
where two independent breast tumors are exposed to cancer pharmacotherapy within a uniform
pharmacokinetic milieu. Both senescence and apoptosis are established responses to therapy; how\
ever, they have potentially variable contributions to the overall outcome of treatment, which are yet
to be determined. Methods: In this report, we describe the clinicopathological picture of two SBBC
cases that received standard anticancer treatment and assess their expression profile of several mo\
lecular hallmarks of senescence and apoptosis. Results: Our analysis identified that synchronous
tumors have variable expression profiles of both senescence\ and apoptosis\associated biomarkers,
despite comparable pathological responses to neoadjuvant chemotherapy and current survival
rates. Conclusions: Our results highlight the variable expression of senescence\ and apoptosis\asso\
ciated markers in breast tumors (despite the shared somatic genetic background) and invites a large\
scale assessment of both senescence and apoptosis in breast cancer tissue in vivo and their contri\
bution to the pathological response and overall survival.
col28050327
Received: 31 August 2021
Keywords: senescence; apoptosis; BCL\2; p16INK4a; chemotherapy; synchronous; bilateral; breast
cancer
Accepted: 28 September 2021
Published: 30 September 2021
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Copyright: ? 2021 by the authors. Li\
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licenses/by/4.0/).
1. Introduction
Synchronous bilateral breast cancer (SBBC) is defined as the diagnosis of two inde\
pendent primary breast cancer lesions (rather than contralateral metastasis) in both
breasts, within an interval of one month to one year [1,2]. Despite the low frequency of
SBBC (0.2%C3% of all breast cancers), the incidence of SBBC has been rising due to im\
proved diagnostic approaches [3,4]. The key risk factors of SBBC include younger age at
presentation [5], a family history of bilateral breast cancer [6], lobular histology [7], multi\
centricity [8], existence of sclerotic disease [4] and BRCA mutations [9]. Furthermore, an
estrogen receptor (ER)\positive and human epidermal growth factor receptor 2 (HER2)\
negative status was reported in the majority of SBBC tumors [10]. The prognosis of SBBC
is largely undetermined, as some evidence supports a worse prognosis [11], while others
suggest that the existence of a synchronous tumor only minimally affects overall survival
Curr. Oncol. 2021, 28, 3836C3845.
journal/curroncol
Curr. Oncol. 2021, 28
3837
[12]. Nonetheless, the five\year survival rate for synchronous breast cancer was around
60%, as opposed to 78.7% in metachronous bilateral breast cancer [5].
While the treatment of patients with SBBC is challenging due to the lack of estab\
lished guidelines specific to the treatment of SBBC [13], many patients receive conven\
tional neoadjuvant chemotherapy (NAC) as part of their therapy. More importantly, SBBC
provides an avenue whereby two independent tumors, exposed to the same pharmaco\
logical cancer therapies, exist within the same pharmacokinetic environment. This allows
for the investigation of several cell stress mechanisms that govern the level of pathological
responses to NAC, especially given that a considerable percentage of patients receiving
NAC fail to develop a complete pathological response (pCR) [14].
In this work, we report two cases of SBBC, of distinct tumor biology, with variable
pathological responses to NAC, and utilize their tumor samples to investigate several bi\
omarkers characteristic of two fundamental cell stress mechanisms: senescence and apop\
tosis. Apoptosis is the primary form of programmed cell death that mediates the cytotoxic
effects of NAC [15,16] and accounts for the ideal development of pCR following pharma\
cotherapy. On the other hand, senescence has been increasingly recognized as a funda\
mental response to anti\cancer therapies [17], and a potential contributor to unfavorable
therapy outcomes [18]. Interestingly, senescent cells are persistent, and resist apoptosis
via upregulating the pro\survival proteins (e.g. BCL\2, BCL\XL) [19], which, consequently,
renders them sensitive to senolytic agents that target these anti\apoptotic molecules [20].
Therefore, the interplay between senescence and apoptosis can partly explain the patho\
logical outcome of a breast tumor following exposure to NAC [21]. Here, we provide evi\
dence that synchronous breast cancer can have variable expression profiles of both senes\
cence\ and apoptosis\associated hallmarks, despite similar initial pathological responses
to NAC. This report is the first to provide a comprehensive assessment of these bi\
omarkers in SBBC cases.
2. Case Presentation
The first case was of a 46\year\old premenopausal woman who presented to the
breast surgery clinic at King Hussain Medical Center with bilateral breast masses with
left\sided skin involvement and left axillary lymph node enlargement (Case 1, Table 1).
Her mammography and ultrasonography revealed a dense mass of 3.1 2.4 cm in size,
with irregular margins in the middle outer aspect of the left breast, enlarged pathological
left axillary lymph nodes, and a lobulated mass of 2.4 1.7 cm in size along the upper
outer quadrant of the right breast, which were classified BI\RADS 4 and 5 for the right
and left breast masses, respectively. The core\needle biopsy of both breast masses estab\
lished the diagnosis of invasive ductal carcinoma of the breast (IDC). Moreover, the im\
munohistochemical analysis of the hormone receptor expression status revealed that the
right\sided breast tumor was positive for ER+, progesterone receptor (PR+) (100% and
30% expression level, respectively), and positive for HER2+. In contrast, the left\sided tu\
mor was positive for both ER+ and PR+ (100% expression level for both), while negative
for HER2\. Furthermore, fine\needle aspiration of the left axilla demonstrated the exist\
ence of malignant cells suggestive of a locally advanced breast carcinoma. However, stag\
ing studies were negative for evidence of distant metastatic disease. Thus, based on the
8th edition of the American Joint Committee on Cancer (AJCC) staging manual, the clini\
cal staging was established as follows: stage IIIB (T4bN1M0) for the left\sided breast tu\
mor and IIA (T2N0M0) for the right\sided breast tumor.
Curr. Oncol. 2021, 28
3838
Table 1. Comparison of different diagnostic and treatment characteristics between the two reported
cases.
Case 1
Case 2
Right
Left
Right
Left
BI\RADS
4
5
5
5
Diagnosis
IDC
IDC
IDC
IDC
Grade
G1
G3
G1
G3
TNM Staging
T2N0M0
T4bN1M0
T2N0M0
T2N2M0
ER+, PR+,
Receptor Status
ER+, PR+, HER2\ ER+, PR+, HER2+ ER+, PR+, HER2\
HER2+
NAC Regimen
A+C (4 cycles) followed by D+T+ P A+C (4 cycles) followed by D+T+ P
Bilateral MRM + axillary lymph Bilateral MRM + axillary lymph nodes
Surgical Intervention
nodes dissection
dissection
ypTNM Staging
ypT1c ypN0
ypT1a ypN1a
ypT1a ypN0
pT1b ypN2a
Radiotherapy 50 Gy over 25 frac\
Radiotherapy 50 Gy over 25 fractions
Adjuvant therapy
tions
trastuzumab and tamoxifen
trastuzumab and tamoxifen
The table describes the clinicopathological characteristics of both tumors, neoadjuvant chemother\
apy, adjuvant therapy regimens and mode of surgical intervention of both reported cases. The
table also presents the intraoperative pathological staging following the completion of treatment
with NAC. Patients information was collected from the databases of King Hussein Medical Cen\
ter based on the approval by the Institutional Board Review (IRB) committee of the Jordanian
Royal Medical Services (JRMS) No. 6/2021 and in accordance with the World Medical Association
Declaration of Helsinki. Both participating subjects provided informed consent. Abbreviations: BI\
RADS: Breast Imaging Reporting and Data System; IDC: invasive ductal carcinoma; G: grade; ER:
estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth receptor 2; A: Adri\
amycin; C: cyclophosphamide; D: docetaxel; T: trastuzumab; P: pertuzumab; MRM: modified radi\
cal mastectomy; Gy: gray.
The second case was a 54\year\old postmenopausal woman who also presented to
the breast clinic at King Hussain Medical Center with bilateral breast masses, associated
with left nipple retraction, peau dorange skin, and palpable axillary lymph nodes (Case
2, Table 1). Her mammography and ultrasonography revealed an irregular mass of 5x3.7
cm in size containing microcalcifications, resulting in tissue distortion and skin thickening
in the upper outer quadrant of the left breast. Moreover, ultrasonography showed en\
larged suspicious lymph nodes in the left axilla, and multiple ill\defined densities (the
largest was 2.5x1.5 cm) with tiny calcifications in the lower inner quadrant of the right
breast, categorized as BIRADS 5 in both breasts. The core\needle biopsy confirmed the
diagnosis of bilateral IDC, whereas nodal metastasis was detected by FNA of the left ax\
illa. The receptor status of the right\sided tumor was ER+, PR+ (100% for both), and
HER2+. In comparison, the left\sided tumor exhibited lower expression of ER+ and PR+
(50% and 30%, respectively), and was negative for HER2\. No evidence of distant metas\
tasis was detected. Accordingly, clinical staging based on the 8th AJCC staging manual
was established as follows: IIIA (T2N2M0) for the left\sided breast tumor and IIA
(T2N0M0) for the right\sided breast tumor.
Following the discussion of the treatment strategy by the onco\surgical multidisci\
plinary team, both patients received four cycles of NAC, namely, adriamycin + cyclophos\
phamide followed by docetaxel, trastuzumab, and pertuzumab. Two months following
the completion of pharmacotherapy, Case 1 underwent a bilateral modified radical mas\
tectomy (MRM) and bilateral axillary lymph node dissection. The histopathology of the
right\sided tumor showed a residual invasive tumor of 17 mm in size, grade 2, 17 axillary
lymph nodes negative for metastasis, no lympho\vascular or perineural invasion, and the
receptor status was ER+, PR+, and HER2+ (ypT1c ypN0) (Table 1). The left side showed a
tiny residual focus of an invasive tumor 2 mm in size, grade 2, two lymph nodes positive
for metastasis out of 13, positive lympho\vascular and not identified perineural invasion,
Curr. Oncol. 2021, 28
3839
and the receptor status was ER+ and PR+ and HER2\ (ypT1a ypN1a). On the other hand,
Case 2 underwent bilateral MRM with axillary lymph node dissection, three months fol\
lowing the completion of pharmacotherapy. The surgical pathology report indicated the
following: 1) right breast: residual tumor of 3 mm in size, grade 1, 22 axillary lymph nodes
were negative for metastasis, no lymphovascular or perineural invasion, and the receptor
status was ER+, PR+ (100% for both), and HER 2+ (ypT1a YpN0) (Table 1); 2) left breast:
residual tumor of 7 mm in size, grade 3, 7 lymph nodes were positive for metastasis out
of 13, lymphovascular and perineural invasion was detected, and the receptor status was
ER+ and PR+ (50% and 30%, respectively), but was negative for HER2\ (ypT1b YpN2a).
Based on the receptor status, both patients were commenced on postoperative
trastuzumab and tamoxifen to decrease the risk of recurrence. Moreover, within three
months of surgical intervention, both patients also received adjuvant radiotherapy with
50 Gy over 25 fractions (Table 1). To date (16 months and 11 months after treatment initi\
ation for Case 1 and Case 2, respectively), both patients have remained asymptomatic,
without clinical or radiological evidence of breast cancer recurrence.
3. Biochemical Analysis
We then wanted to look at the expression level of several biomarkers associated with
both senescence and apoptosis, aiming to identify variabilities in their expression level in
SBBC, and whether it is linked to tumor response to therapy. For that, we employed im\
munohistochemistry techniques to detect and quantify the expression of these protein
markers using true\cut and core\needle biopsy tumor (T) blocks for both cases, as de\
scribed previously [22] (Figure 1). For comparison, we also provided an assessment of
protein expression levels in normal breast epithelium (N) for each corresponding breast
of both cases (Figure 1). The examined senescence\associated markers included: p16INK4a,
p21Cip1, Ki67, Lamin B1, histone 3 lysine 9 tri\methylated (H3K9Me3) and vascular endo\
thelial growth factor (VEGF) [23], while the examined apoptosis markers were: p53,
NOXA, MCL\1, BAX, BCL\XL [24].
For senescence, in Case 1, the right tumor was positive for p21Cip1 (T: 60%, N: 80%),
Ki67 (T: 35%, N: negative), Lamin B1 (T: 60%, N: 80%), and H3K9Me3 (T: 60%, N: 90%)
(Table 2). Similarly, the left tumor was positive for p21Cip1 (T: 5%, N: 50%), Ki67 (T: 65%,
N: negative), Lamin B1 (T: 50%, N: 10%), and H3K9Me3 (T: ................
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